Childhood lead (Pb2+) intoxication remains a public health problem of global proportion. A number of studies over several decades have consistently shown that one of the most prominent effects of Pb2+ in children is to decrease their capacity to learn with devastating effects on cognitive and intellectual development. The consequences of childhood Pb2+ intoxication on the intellectual capacity of pediatric populations and society as a whole is incalculable as the world is more and more dominated by knowledge- based economy. Recent human studies have also shown that previous Pb2+ exposure is associated with longitudinal declines in cognitive function and loss of brain volume in aging individuals. Therefore, Pb2+ exposure in early life has immediate and long-term consequences to human neurological health. The long-term goal of the proposed studies is to understand the behavioral, cellular and molecular bases of Pb2+-induced deficits in cognitive function in developing animals. The ultimate goal is to define molecular mechanisms by which Pb2+ exposure impairs intellectual development in order to devise therapeutic strategies that may be beneficial to Pb2+ intoxicated children. The proposed studies will delineate mechanism(s) by which Pb2+ affects NMDA receptor mediated processes in developing synapses. This will be performed in primary culture of hippocampal neurons. We will also examine the cellular (neurogenesis) and molecular (NMDA receptor) bases of how environmental enrichment and voluntary exercise may reverse the learning deficits of Pb2+ exposed developing animals. Finally, we will begin to assess the neurological consequences of combined developmental Pb2+ exposure and stress. We will examine their combined effects within the context of learning and underlying neurobiological substrates. Previous studies have only examined the effects of Pb2+ on the developing brain without taking into consideration the context in which Pb2+ intoxication occurs. Therefore, the proposed studies will provide a greater relevance to the human condition. Relevance: Scientific evidence has demonstrated that changes in the way that central nervous system synapses develop or deficits in synaptic proteins, forms the bases for many neurological, psychiatric and neurodegenerative diseases. The proposed studies will help delineate molecular mechanisms by which Pb2+ intoxication alters synapse development. These studies will provide the basis for the testing of therapeutic strategies such as environmental enrichment and voluntary exercise on reversing the well-characterized learning deficits in Pb2+ intoxicated animals. Pediatric populations that are most likely to experience Pb2+ intoxication are the same ones that also experience stressful, low-socioeconomic conditions. Therefore, one of the stated goals of our project is to examine the relationship of Pb2+ exposure and stress on neurodevelopment. The proposed studies will have significant implications to public health policy as well as therapeutic interventions for Pb2+ intoxicated children. PUBLIC HEALTH RELEVANCE: The long-term goal of the proposed studies is to understand the behavioral, cellular and molecular basis of lead (Pb2+)-induced deficits in cognitive function in developing animals. The ultimate goal is to examine the detrimental effects of Pb2+ on cellular and molecular processes that depend upon activation of the NMDA receptor and how stress may influence such interactions, and to devise targeted therapeutic strategies to reverse these deficits. A major advantage of this unique team of multidisciplinary collaborators is that we will examine the effects of Pb2+ at the behavioral, systems, cellular and molecular levels in animals that are intoxicated with environmentally relevant levels of Pb2+.